In May 2006, McGuinness signed an exclusive two-year contract with Marvel Comics. His first printed Marvel piece was a cover for the Marvel limited series Civil War, and featured Thor in his original outfit. He also drew a variant cover for the monumental Captain America #25. McGuinness's first ongoing story under his new Marvel Contract was a 12-page Ultimate back-up featuring the Hulk vs. Wolverine.

Beginning in 2008, McGuinness drew the first six issues of a new Hulk series, during which he and writer Jeph Loeb introduced a new archenemy, Red Hulk. McGuinness would sporadically draw 11 more issues of the series until issue #30 (April 2011). Loeb characterized McGuinness' art style thus: "He takes a little bit of Kirby, a taste of Arthur Adams, and then adds his own unique spin and it's awesome."[5]

^Cowsill "2000s" in Dolan, p. 300: "The multipart story 'Our Worlds at War' dominated the Superman books for the August and September [2001] cover dates...The opening chapter, written by Jeph Loeb and drawn by Ed McGuinness, began with Superman investigating the missing Pluto."

^Cowsill "2000s" in Dolan, p. 311: "Writer Jeph Loeb and artist Ed McGuinness created a tale befitting such A-list characters in 'Public Enemies', the six-part story that launched the new series."